Mitochondrial autophagy in diabetes-related cognitive decline and skin ulcers: Mechanistic insights and therapeutic implications

Abstract

Diabetic skin ulcers significantly reduce the quality of life of patients with diabetes, and diabetes-related cognitive impairment is a cognitive deterioration that happens along the course of diabetes. Mitochondrial dysfunction is a major pathophysiology of skin ulcers and cognitive deterioration associated with diabetes. An essential component of the mitochondrial quality control system is mitochondrial autophagy, which aids in the removal of faulty mitochondria; preserving the health and regular operation of mitochondria requires both the preservation of mitochondrial function and the preservation of mitochondrial quality and activity. This review highlights key mitophagy pathways, including PINK1/Parkin-dependent and receptor-mediated mechanisms, and emphasizes their differential roles in diabetes-related cognitive impairment and skin ulcer healing, thereby providing a mechanistic framework for the development of targeted mitophagy-based therapeutic strategies.

Key Words: Diabetes mellitus; Mitochondrial autophagy; Cognitive impairment; Reactive oxygen species; Skin ulcers

Core Tip: The mechanism of mitochondrial autophagy in skin ulcers and cognitive decline associated with diabetes is the main topic of this review. This study aimed to clarify the crucial role of mitochondrial autophagy in maintaining the metabolic balance of cells, provide potential therapeutic strategies and intervention methods, and offer new concepts for the clinical management of diabetes-related complications. It also examined how mitochondrial autophagy reduces neurodegeneration brought on by diabetes and supports the molecular pathway of skin healing by removing damaged mitochondria.

INTRODUCTION

One common consequence of diabetes is cognitive impairment[1-3]. Diabetes greatly raises the incidence of cognitive impairment-related diseases[4-8]. It has been reported that diabetes raises the risk of Alzheimer's disease (AD) by 1.43 times, vascular dementia by 1.91 times, and dementia from all causes by 1.25 times[9]. Patients with diabetes and cognitive impairment, particularly those who are young or elderly, have a lower quality of life and a higher financial burden. This impacts their neurological development, worsens disability, and adds to the strain of family care[10-12]. Likewise, diabetic skin ulcers are another terrible consequence, and their weakened wound-healing systems lead to high morbidity and medical expenses.

Due to impaired mitophagy (mitochondrial-selective autophagy) activity, damaged mitochondria build up in individuals with diabetes, exacerbating tissue damage and cellular dysfunction. Inadequate mitophagy, particularly in skin tissue, can impede keratinocyte and fibroblast activity, interfere with wound healing, and result in the development of persistent skin ulcers. In addition, diabetes-related vasculopathy and neuropathy can potentially worsen the occurrence and progression of skin ulcers by altering the local blood supply and nerve transmission.

Mitochondrial dysfunction has drawn more attention in relation to diabetes-related cognitive impairment[13-16]. The survival and activity of neurons, which are heavily reliant on energy, form the foundation of cognitive function[17]. At the same time, sufficient energy availability and tolerance to oxidative stress are necessary for glial-neuron metabolic interactions, such as neurotransmitter reuptake and energy substrate transfer. In addition to producing energy, mitochondria also control intracellular Ca²⁺ homeostasis, generate reactive oxygen species (ROS), and take part in vital cellular functions that maintain cell viability, such as apoptosis and the immune response[18-20]. As a kind of selective autophagy in cells, mitophagy is an essential component of the mitochondrial quality control system[21-23]. Mitophagy preserves the number and caliber of healthy mitochondria and safeguards mitochondrial function by eliminating damaged mitochondria in a targeted manner[24-26]. One of the processes that results in aberrant mitochondrial function is defective mitophagy[27-30].

Even while the significance of mitophagy in diabetes complications is becoming more widely acknowledged, there are still a number of unanswered questions about the precise pathways relating to mitophagy failure and the development of skin ulcers and cognitive deterioration. The best therapeutic modulation techniques are yet unknown, and the directional changes in mitophagy across various diabetes situations are contradictory. Therefore, this review aims to systematically summarize the regulatory mechanisms of mitophagy in diabetes-related cognitive impairment and skin ulcers, with a particular focus on pathway-specific alterations, tissue heterogeneity, and their implications for therapeutic targeting.

OVERVIEW OF AUTOPHAGY AND MITOPHAGY MECHANISMS

The self-defense mechanism against radiation, oxidative stress, hypoxia, nutritional deficiencies, and foreign microbes is autophagy, a catabolic process that sends the cell's cytoplasmic components-including proteins, organelles, aggregates, and any other intracellular material-to lysosomes for breakdown[31-33]. Macrophage, microautophagy, and chaperone-mediated autophagy are all forms of autophagy[34]. In general, autophagy is synonymous with macroautophagy, a process that involves the formation of a double-layered membrane autophagosome to consume damaged organelles or biochemical molecules. This autophagolysosome subsequently combines with the lysosome to break down the phagocyte[35-38]. Under normal circumstances, cellular autophagy levels stay low, allowing cells to preserve the circulation and regeneration of cell material, get rid of substances that induce cell death, and keep the cellular environment in a state of homeostasis. In order to maintain the energy supply, autophagy becomes highly active during stress, and nonselective autophagy degrades excess 3 proteins in cells (Figure 1).

Figure 1 Autophagy- and obesity-mediated diabetes progression. Illustrations of the relationships among obesity, impaired autophagy, and diabetes development. Under obesity-related conditions, dysregulated autophagy pathways contribute to metabolic dysfunction through multiple mechanisms. The key molecular modulators shown include PPARGC1A (involved in mitochondrial biogenesis and cellular energy metabolism), AMPK (regulating cellular energy status and autophagy initiation), and UCP1 (involved in thermogenesis and energy expenditure). The cellular autophagy machinery, including autophagosome formation and lysosomal degradation processes, becomes compromised in obesity, leading to the accumulation of damaged organelles and metabolic stress. This autophagy dysfunction promotes insulin resistance, inflammation, and ultimately progression to type 2 diabetes mellitus. The figure demonstrates how obesity creates a pathological environment that disrupts normal cellular quality control mechanisms, contributing to the development of diabetic complications. This figure was created by BioRender.com (Supplementary material).

MITOPHAGY REPRESENTS THE SELECTIVE AUTOPHAGY OF DAMAGED MITOCHONDRIA

Following identification and labeling of damaged mitochondria, light chain 3 (LC3), a microtubule-associated protein necessary for autophagy, changes from cytoplasmic soluble LC3I to membrane-type LC3II. This latter is the primary constituent of the bilayer structure of mature autophagosomes and is enlisted to form autophagosomes surrounding damaged mitochondria[39-42]. By binding to proteins tagged on the mitochondrial surface, LC3II phosphorylates ubiquitin (UB) via the phagophore assembly site (PAS). Mitophagosomes are later formed by engulfing damaged mitochondria, and these cells work in tandem with lysosomes to degrade damaged mitochondria[43-45]. Cell damage is the result of insufficient mitophagy, which causes damaged mitochondria to accumulate and ROS levels to rise[46]. Furthermore, lysosomes can release a number of proteases in response to excessive mitophagy, which can result in the improper removal of healthy mitochondria and ultimately cell death[47-50]. Sustaining mitochondrial function and cell viability requires balanced mitophagy (Figure 2). Thus, scientists have been concentrating on the ideal amount of mitophagy and how to balance it.

Figure 2 Autoimmune destruction of pancreatic β cells in type 1 diabetes. The diagram illustrates the pathophysiology of type 1 diabetes mellitus, showing the progressive autoimmune attack on insulin-producing β cells within the pancreatic islets of Langerhans (left panel). The normal pancreatic islet architecture contains α cells (producing glucagon), β cells (producing insulin), and δ cells (producing somatostatin) (middle panel). In type 1 diabetes, autoreactive cytotoxic T cells recognize β cell-specific antigens and mount an immune attack against insulin-producing cells, whereas α and δ cells remain largely unaffected (right panel). The end result of this autoimmune process is the selective destruction of β cells, leading to complete insulin deficiency, whereas glucagon and somatostatin production from α and δ cells continues. This autoimmune-mediated β-cell destruction results in the characteristic hyperglycemia and insulin dependence observed in type 1 diabetes patients. This figure was created by BioRender.com (Supplementary material).

MITOPHAGY IS CARRIED OUT MAINLY THROUGH UB-DRIVEN PATHWAYS AND RECEPTOR-MEDIATED PATHWAYS

The most traditional method of initiating mitophagy is PINK1/PARKIN-mediated[51-53]. PINK1, a mitochondrial serine/threonine kinase, is physiologically transported by the translocation complex translocase in the outer membrane of the mitochondria to the intermembrane space and then by the inner mitochondrial membrane (IMM) translocase to the IMM[54-56]. Once in the IMM, PINK1 is released into the cytoplasm for destruction after being cleaved by mitochondrial matrix proteases[57-60]. PARKIN is activated by p-UB, which is created when PINK1 phosphorylates UB at Ser65[61-64]. By altering the UB chains of mitochondria, which PINK1 phosphorylates successively, PARKIN, a crucial UB E3 ligase, enhances the original signal and establishes a positive feedback loop with PINK1[65]. Autophagy-associated proteins are drawn to the vicinity of mitochondria when p-Ser65 chains build up on the outer mitochondrial membrane[66-68]. It has been shown that the multiubiquitination signal in PINK1/PARKIN-mediated mitophagy is recognized by proteins such SQSTM1/p62, the UB-binding protein p62, NBR1, NDP52, OPTN, and TAX1BP1[69-72]. Both the UB binding domain and the LC3 interaction region (LIR) are present in the aforementioned autophagy-associated proteins, and they bind to the UB chain on the target mitochondria[73-75]. The autophagy initiation factor ULK1, FYVE and coiled-coil DFCP1, and WIPI1 are then enlisted to encourage the formation of autophagosomes surrounding mitochondria[76-78]. Among them, SQSTM1/p62 has been frequently employed in conjunction with LC3II as a measure of autophagic flux and has long been linked to selective autophagy, including mitophagy[79-83].

Proteins with LIR motifs on mitochondrial membranes are involved in receptor-mediated mitophagy. In certain circumstances and cell types, these proteins act as mitophagy receptors by binding directly to the PAS and enabling direct interactions between mitochondria and LC3 or other members of the LC3/GABA receptor-associated protein (GABARAP) family to form mitophagosomes[84-90]. BCL2 adenovirus E1B 19 kDa interacting protein 3 (BNIP3) and its analogs BNIP3 L (NIX), BCL2 L13, FUNDC1, anti-mitochondrial antibody-related autophagy and Beclin-1-regulated autophagy protein 1 (AMBRA1), PHB2, and cardiolipin are among the proteins that have been shown to act as mitophagy receptors thus far (Figures 3 and 4).

Figure 3 Classification of obesity phenotypes on the basis of metabolic health and body mass index. The diagram illustrates the heterogeneous nature of obesity by categorizing individuals into four distinct phenotypes on the basis of diabetes/cardiovascular disease risk and body mass index (BMI). The classification includes the following: (1) Metabolically unhealthy obese: Characterized by increased adiposity, inflammation, adipose tissue dysfunction, and insulin resistance, with predominant visceral fat distribution and reduced lipid storage capacity in the liver and skeletal muscle; (2) Metabolically healthy obese: Featuring increased adiposity but preserved metabolic function, predominantly subcutaneous fat distribution, and maintained lipid storage capacity; (3) Metabolically unhealthy normal-weight/metabolically obese normal-weight: Normal BMI individuals with metabolic dysfunction; and (4) Metabolically healthy nonobese: Normal weight individuals with healthy metabolic profiles. This phenotypic classification demonstrated that metabolic health status does not always correlate directly with BMI, highlighting the importance of adipose tissue distribution and function rather than total body weight in determining diabetes and cardiovascular disease risk. MUO: Metabolically unhealthy obese; MHO: Metabolically healthy obese; MUNO/MONW: Metabolically unhealthy normal-weight/metabolically obese normal-weight; MHNO: Metabolically healthy nonobese. This figure was created by BioRender.com (Supplementary material).

Figure 4 Autophagy signaling pathways and molecular machinery in diabetes. The diagram illustrates the key regulatory mechanisms controlling autophagy under diabetic conditions (upper panel). Two major signaling pathways regulate autophagy initiation: The PI3K signaling pathway (left), which involves BCR, PI3K, and the ULK1 complex, and the mTOR signaling pathway (right), which involves p53, mTOR, and downstream PI3K/AKT and MAPK/ERK pathways that respond to cellular stress and nutrient availability (middle panel). The autophagy process proceeds through four sequential stages: Initiation of phagophore formation, elongation of the isolation membrane, maturation into a complete autophagosome, and finally, autophagosome formation (lower panel). Two critical molecular systems execute autophagy: The ATG12 system (left), involving ATG12, ATG5, and ATG16 L conjugation through ATG10, ATG16, and ATG7, and the ATG8 system (right), featuring LC3 processing from LC3-I to LC3-II through ATG4-mediated cleavage and ATG7/ATG3-dependent conjugation. This molecular machinery is essential for autophagosome formation and is frequently dysregulated in diabetic conditions, contributing to impaired cellular quality control and metabolic dysfunction. This figure was created by BioRender.com (Supplementary material).

Importantly, these two mitophagy pathways appear to be regulated differently in diabetes and may therefore contribute to tissue-specific complications. Under chronic hyperglycemia, mitochondrial oxidative stress and impaired mitochondrial quality control have been repeatedly implicated in diabetes-associated neurocognitive impairment. In this context, disruption of the PINK1/Parkin axis-either through insufficient PINK1 accumulation on the outer mitochondrial membrane or inefficient Parkin recruitment-may compromise ubiquitination of damaged mitochondria and weaken mitophagic clearance, thereby favoring persistent mitochondrial dysfunction and ROS burden in the central nervous system[40,75,84]. Experimental evidence in diabetic models further supports that high-glucose conditions can suppress neuronal mitophagy and aggravate cognitive deficits, consistent with a potential role of PINK1/Parkin-related mitophagy impairment in diabetes-related cognitive decline[63,66,76].

By comparison, receptor-mediated mitophagy pathways (e.g., FUNDC1-, BNIP3/BNIP3 L-associated mechanisms) are often discussed in connection with hypoxia/inflammation-driven stress responses and metabolic perturbations, which are also common features across multiple diabetic complications[84,87,89]. Given that ischemia/hypoxia and inflammatory activation are central components of difficult-to-heal diabetic ulcers and related peripheral tissue injury, dysregulated receptor-mediated mitophagy could plausibly limit stress-adaptive mitochondrial turnover and thereby interfere with cellular repair programs under diabetic conditions[56,75]. Although direct mechanistic evidence may differ across tissues, the overall framework that “distinct mitophagy routes respond to distinct pathological cues” provides a useful lens to interpret heterogeneous diabetic complications[87,89].

Therefore, distinguishing between UB-dependent and receptor-mediated mitophagy may help explain why mitophagy-related alterations manifest differently in the central nervous system vs peripheral tissues under diabetic conditions[84-87].

MITOPHAGY'S FUNCTION AND MECHANISM IN DIABETES-RELATED COGNITIVE DECLINE

In addition to the brain damage brought on by diabetes, such as insulin resistance, hyperglycemia, and hypoglycemia, diabetes-related cognitive impairment also includes AD and vascular cognitive impairment (VCI), which are directly linked to the onset of diabetes[91-95]. There are parallels and differences in the function of mitophagy in various cognitive diseases. In addition to experimental and animal studies, emerging evidence from human investigations also supports the involvement of mitophagy dysregulation in diabetes-related cognitive impairment. Clinical and observational studies have reported alterations in autophagy- and mitophagy-associated biomarkers in peripheral blood or cerebrospinal fluid of patients with cognitive dysfunction, suggesting compromised mitochondrial quality control in the human central nervous system[20,39]. Moreover, studies in patients with diabetes have demonstrated close associations between metabolic dysregulation, mitochondrial dysfunction, and cognitive decline, indirectly implicating impaired mitophagy in disease progression. Although direct assessment of mitophagy activity in human brain tissue remains technically challenging, these clinical findings provide important translational support for the relevance of mitophagy in diabetes-associated cognitive decline[87,93].

HYPERGLYCEMIA-RELATED COGNITIVE IMPAIRMENT

In various stages of the same disease, mitophagy is a dynamic process that can be strengthened or inhibited[96-98]. Although there are currently few thorough studies on the role of mitophagy status in hyperglycemia-induced cognitive impairment, what is known indicates that mitophagy disruption is linked to cognitive impairment in diabetes[99-104]. Proteins whose expression significantly changed in peripheral blood platelets were significantly enriched in the dysregulated mitophagy/autophagy pathway, according to a clinical study[105] of diabetes patients with mild cognitive impairment (MCI) that used proteomics to investigate peripheral blood markers of type 2 diabetes mellitus (T2DM) patients with MCI. OPTN, SQSTM1, and TBC1D15 are some of these proteins. A strong correlation was found between a decrease in the MMSE score and an increase in OPTN, which facilitates the initiation of mitophagy. This suggests that T2DM patients with MCI may activate mitophagy mediated by OPTN[106-110]. These results imply that elevated OPTN may be a distinguishing factor between patients with T2DM-MCI and T2DM-nMCI[111-114]. However, there are still significant unknowns regarding the state of mitophagy in the central nervous system, and mitophagy markers in peripheral blood only offer circumstantial evidence.

Patients with type 1 diabetes who had consistently poor glucose control and reported brain tissue abnormalities and neuronal degeneration were evaluated for brain injury in one postmortem research[115]. Increased LC3 levels and ATG7 expression were found in one investigation, indicating a possible role for autophagy system activation in diabetic brain neuronal injury[116-120]. Although the cellular autophagy system's activation implies that mitophagy may also be engaged, the mitophagy state in the central nervous system of diabetic patients has not been explicitly investigated in humans. However, mitophagy-specific markers are needed to validate this assumption.

Constant exposure to high blood sugar impairs mitochondrial activity and, by generating too many ROS, encourages oxidative stress and neuroinflammation[121-126]. The mechanisms of mitophagy-mediated mitochondrial dysfunction have been uncovered by a number of fundamental investigations[127-130]. When synaptic integrity and autophagy in the cortex and hippocampus of 3xTg-AD and T2DM model mice were investigated, researchers observed that brain damage in the two groups was identical[131-134]. It was suggested that the autophagy-mediated lysosomal system was impeded by the decreased expression of ATG7 and LAMP1[135]. Although this study only looked at macroautophagy markers rather than mitophagy-specific indicators, it did find similarities between AD and diabetic brain damage in terms of mitochondrial dysfunction.

The expression of PINK1/PARKIN, which are essential proteins for mitophagy, was downregulated, and autophagic flux was compromised, according to a later study[136] that examined alterations in mitophagy in PC12 brain cell lines grown in vitro under high glucose conditions. The decrease in PINK1/PARKIN-mediated mitophagy in nerve cells under high glucose conditions was further supported by the observation of decreased colocalization between the mitochondrial marker protein COX IV and LAMP2[137-140]. Furthermore, in PC12 cells grown with high glucose, increasing FUNDC1-mediated mitophagy reduced mitochondrial dysfunction and increased cell resilience to oxidative stress and inflammation caused by ROS[141-147]. These findings imply that FUNDC1-mediated mitophagy plays a protective role in the mitochondrial dysfunction produced by high glucose.

While research on animals and cells have shown that the mitophagy system is inhibited, the mitophagy system is activated in hyperglycemia-related cognitive impairment[148-150]. The complicated and dynamic nature of mitophagy, which is impacted by a number of factors such as age, the duration of the disease, blood glucose regulation patterns, and study participant problems, may be reflected in this seeming contradiction. There are difficulties in simulating hyperglycemia models in their entirety, and different experimental methodologies may differ[151-156]. Nevertheless, these experimental studies have provided vital insights into the impact of hyperglycemia on central nervous system autophagy and particular mechanisms of mitophagy failure, affording important indications for clinical study.

COGNITIVE IMPAIRMENT ASSOCIATED WITH HYPOGLYCEMIA AND BLOOD SUGAR FLUCTUATIONS

Patients with diabetes who experience hypoglycemia frequently experience complications during glycemic treatment, and the development of hypoglycemia can raise their risk of cognitive impairment[157-160]. The pathogenesis of cognitive impairment in diabetics with hypoglycemia is significantly influenced by mitochondrial dysfunction[161-164]. The majority of research has been on cellular-level autophagy, with relatively few studies examining the connection between hypoglycemia-induced mitochondrial malfunction in central nervous system cells and mitophagy dysfunction[165-168]. Similar to high glucose reperfusion after hypoglycemic episodes, blood sugar levels in diabetic patients can rise sharply above normal levels after hypoglycemia[169]. According to research, elevated levels of LC3II and p62 occur together with autophagy inhibition in the rat hippocampal and cerebral cortex during acute hypoglycemia[170-174]. Activating autophagy can lessen cell damage. Another study showed that in mouse neuroblastoma cell lines (Neuro-2A), autophagy was activated and LC3II levels rose following glucose deprivation, but autophagy was blocked during hyperglycemic reperfusion, which resulted in cell death[175-178]. According to these investigations, autophagy suppression exacerbated damage to nerve cells[179]. Although there aren't many comprehensive research on how mitophagy failure contributes to hypoglycemia cognitive impairment in diabetes, those that do exist offer crucial hints: Impaired cellular autophagic flux could suggest that impaired mitophagy flux plays a role in the pathogenesis of cognitive impairment brought on by mitochondrial malfunction linked to hypoglycemia[180-182]. For a variety of reasons, including irregular medication, an irregular food, and high glucose reperfusion following recovery from hypoglycemia, diabetic patients may have blood sugar variations during glycemic treatment[183-186]. Cognitive disturbance in diabetic individuals has been associated with blood sugar variations[187]. Nevertheless, it is still unknown how blood glucose fluctuations and mitochondrial dysfunction relate to one another in people with cognitive impairment[188]. Research has connected changes in glucose to neural mitochondrial dysfunction, which includes increased formation of ROS in the mitochondria, decreased activity of manganese-dependent superoxide dismutase, and decreased mitochondrial membrane potential[189-192]. Although neuronal studies have not fully examined the role of mitophagy dysfunction in the cognitive impairment linked to blood glucose fluctuations, researchers have found that extreme blood glucose fluctuations can reduce mitophagy, leading to mitochondrial dysfunction in other cell types[193]. Therefore, we speculate that mitochondrial dysfunction and cognitive impairment associated with blood glucose variations may be caused by impaired mitophagy; however, further research is required to clarify the function and mechanism of mitophagy in this setting.

INSULIN RESISTANCE AND AD

The most prevalent neurodegenerative disease, AD, shares a pathophysiology with type 2 diabetes and is frequently referred to as “type 3 diabetes” due to its central insulin resistance and decreased brain glucose metabolism[194]. Reduced mitochondrial oxidative phosphorylation capability, decreased ATP generation, elevated oxidative stress, and unbalanced mitochondrial quality control systems are all hallmarks of mitochondrial dysfunction, which is common in T2DM and AD[195]. In reaction to neurons' intake of glucose, insulin signaling controls mitochondrial activity[196]. The cognitive impairment linked to type 2 diabetes, oxidative stress, and neuroinflammation in AD, as well as neurodegeneration, can all be exacerbated by inadequate insulin signaling in insulin resistance, which can affect mitochondrial function and quality control[197-200]. One crucial element of the mitochondrial quality control system is mitophagy. Examining how aberrant mitophagy contributes to the pathogenesis of AD offers important new information about the mechanisms underlying type 2 diabetes patients’ cognitive decline.

Much attention has been paid to mitochondrial dysfunction in AD brought on by mitophagy problems and how it contributes to the emergence of cognitive impairment[201]. The postmortem hippocampus tissue of AD patients, AD model mice, and AD-like mouse neuronal cell cultures has been found to exhibit abnormalities in mitophagy[202]. The primary manifestation of aberrant mitophagy in AD is “ineffective autophagy”, which is brought on by a disruption in mitophagy activities and the buildup of damaged mitochondria and mitochondrial debris. Intracellular neurofibrillary tangles, which are mostly made up of extracellular beta-amyloid protein (Aβ) plaques and hyperphosphorylated tau protein (p-tau), are among the primary pathogenic characteristics of AD[203-205]. P-tau and Aβ cause excessive mitochondrial fragmentation and the formation of free radicals through their aberrant interactions with mitochondrial proteins, including VDAC1 and DRP1. Reduced mitophagy hinders the removal of damaged mitochondria and mitochondrial fragments, which leads to the accumulation of damaged mitochondria and a decrease in mitochondrial ATP generation. This impairs physiological functions that depend on cellular energy and ultimately leads to cell death.

It's interesting to note that mitophagy activation might happen early in AD. Research shows higher lysosomal and mitophagy-related gene expression in the CA1 region of the hippocampus, along with raised levels of p62 and LC3 in damaged mitochondria and increased recruitment of PARKIN[206-208]. This could be a neuron's compensating reaction to harmful proteins. Mitophagy progressively becomes dysfunctional and disorganized with aging and disease progression. Cell models, AD patient brains, and animal models have all shown decreased levels of PINK1/PARKIN, BCL2 L13, and BNIP3 L/NIX. Additionally, mitophagy initiating proteins, including phosphorylated ULK1, and p-TBK1 are inhibited. Additionally, through aberrant interactions with PARKIN, Aβ and p-tau can interfere with mitophagy.

Furthermore, in the brains of AD patients, the buildup of mitochondrial debris brought on by damaged mitochondria and inadequate mitophagy impacts not only neurons but also microglia and astrocytes. Damaged and defective mitochondria build up in microglia of APP/PS1 double-transgenic AD model mice, impairing phagocytosis and Aβ plaque removal[209]. Astrocytes and neurons undergo mitochondrial transfer, in which the astrocytes take defective mitochondria from the neurons, complete mitochondrial rejuvenation by mitophagy and mitochondrial biosynthesis, and then transfer healthy mitochondria to the neurons. Because astrocytic mitophagy is compromised in AD, astrocytes’ capacity to sustain neurons is diminished.

Based on these findings, we postulate that although early AD is characterized by a transient compensatory mitophagy activation, as the disease progresses to the decompensation stage, several significant cell types in the central nervous system experience mitophagy abnormalities. Mitophagy activation might be a useful strategy for treating AD patients' cognitive impairment.

VCI

Diabetes is one risk factor for cerebrovascular disease, and atherosclerosis is a chronic consequence of diabetes. From moderate cognitive impairment to dementia, VCI encompasses a range of symptoms brought on by cerebral hemorrhage, cerebral infarction, and other cerebrovascular illnesses and associated risk factors[210]. The two primary mechanisms of injury are chronic cerebral hypoperfusion (CCH) and cerebral ischemia-reperfusion injury (I/R). Cognitive dysfunction may result from the inflammatory response, oxidative stress, energy supply disruptions, and synapse loss, among other pathways of cerebral ischemia injury. These many processes entail mitochondrial dysfunction.

Ischemic brain damage is influenced by mitophagy, a vital physiological process that maintains the quantity and quality of mitochondria. However, during I/R damage, increased mitophagy encourages neuronal death. Mitophagy levels progressively rise after early I/R injury, and active mitophagy lowers intracellular oxidative stress levels by stopping defective mitochondria from producing ROS. Twenty-four hours after I/R damage, mitophagy activity peaks and then declines. Later phases of I/R injury may cause mitophagy to deteriorate, however stimulation of mitophagy during this period can have some neuroprotective effects via the PINK1/PARKIN, FUNDC1, BNIP3 L/NIX, and other pathways. Mitophagy appears to decline in CCH damage, following patterns seen in AD. Instead of the traditional UB pathway, BNIP3-mediated mitophagy reduction may be the primary cause of neuronal damage under prolonged hypoxia.

THERAPEUTIC STRATEGIES TARGETING MITOPHAGY IN DIABETES-RELATED COGNITIVE DISORDERS

The pathophysiology of diabetes-related cognitive impairment has been shown to involve mitochondrial dysfunction mediated by mitophagy malfunction. Thus, encouraging proper mitophagy activation or avoiding excessive mitophagy will offer new approaches to preserving mitochondrial function, reducing damage to the central nervous system, and preventing and treating cognitive impairment. Nowadays, the main methods for promoting mitophagy are targeted control of genes linked to mitophagy or pharmaceutical intervention[211].

The classic autophagy activator rapamycin (RAPA) has been shown to enhance mitochondrial function and decrease mitochondria-dependent apoptosis in AD model mice (level C evidence). RAPA does this by inhibiting the activity of the mTOR and activating AMPK to mediate autophagy and mitophagy. It dramatically lessens the cognitive impairments and impairment of synaptic plasticity brought on by AD. Other medications that increase mitophagy by generally boosting cellular autophagy include metformin (level B proof for diabetes applications) and NAD⁺ precursors. Although there is currently little evidence linking urolithin A and substances like spermidine to cognitive impairment caused by diabetes, they can directly increase the expression of key proteins in the UB and receptor pathways, which facilitates the start of mitophagy (level C evidence). Further mitophagy-regulating medications, such as resveratrol, melatonin, and glucagon-like peptide-1 receptor agonists, are being investigated for the treatment of diabetes-related cognitive impairment (level B-C evidence).

Some researchers have successfully improved AD-related cognitive impairment by activating mitophagy through focused intervention in the PINK1/PARKIN pathway, which relates to the tailored regulation of important mitophagy proteins. In mice with APP-induced AD, stereotactic injection of PINK1-overexpressing vectors into the hippocampus to stimulate mitophagy alleviated mitochondrial dysfunction and markedly decreased oxidative stress, synaptic dysfunction, amyloid-related pathology, and hippocampus Aβ levels. The cognitive impairments and pathological alterations in the hippocampus brought on by intraventricular STZ injection can be avoided by adenovirus-mediated PINK1 overexpression, while PINK1 deletion considerably worsens damage. In contrast to control mice, APP/PS1 mice that overexpressed PARKIN showed enhanced cognitive function, decreased Aβ-amyloid burden, and downregulated APP protein production. To fully understand the role of additional receptor-mediated mitophagy pathways in diabetes-related cognitive impairment, more study is required, as studies on targeted therapies for these pathways are still lacking[212].

Mutations in the HOPS complex subunit have been linked to diabetes; these mutations may affect insulin production and autophagy, upsetting the glucose metabolic balance. Subunit mutations in the HOPS complex, which is necessary for lysosomal fusion, may result in inadequate insulin secretion or islet beta-cell malfunction, which could cause or worsen diabetes. By altering autophagy processes, HOPS complex anomalies may exacerbate the development of diabetes by increasing stress responses and islet beta-cell destruction. Though more research is needed to determine any direct links between neuronal and skin mitophagy, these findings offer fresh insights into the etiology of diabetes and lay the groundwork for future studies of possible treatment targets (Figure 5).

Figure 5 The homotypic fusion and protein sorting complex functions in autophagy-lysosome system fusion and diabetes pathogenesis. The diagram illustrates the critical role of the homotypic fusion and protein sorting (HOPS) complex in lysosomal fusion processes under normal and pathological conditions (upper panel). The normal HOPS complex facilitates proper vesicle trafficking and fusion events, including endocytic vesicle maturation through early and late endosomes and successful autophagosome-lysosome fusion to form autolysosomes for cargo degradation. The intact HOPS complex (shown in detail on the right) contains multiple subunits that coordinate membrane tethering and fusion (lower panel). Mutating the HOPS complex results in impaired autophagosome-lysosome fusion, leading to the accumulation of undigested autophagosomes and defective lysosomal function. This dysfunction disrupts cellular quality control mechanisms and may contribute to diabetes pathogenesis by affecting pancreatic β-cell autophagy, insulin secretion, and glucose metabolism. HOPS complex mutations represent a potential link between autophagy dysfunction and diabetes development, although the specific connections to neuronal and skin mitophagy in diabetic complications require further investigation. This figure was created by BioRender.com (Supplementary material).

ROLE AND MECHANISM OF MITOPHAGY IN DIABETIC SKIN ULCERS

A particular type of selective autophagy called mitophagy is crucial for studying skin ulcers brought on by diabetes. One of the main causes of diabetic skin ulcers is mitochondrial damage brought on by the oxidative stress and inflammation that hyperglycemia frequently causes in diabetic individuals. By lowering oxidative stress, preserving intracellular energy balance, and selectively eliminating damaged mitochondria, mitophagy mitigates these pathogenic alterations[120-123].

Normal cellular metabolic progression is ensured by mitophagy's effective identification and removal of damaged or defective mitochondria. However, conditions like insulin resistance and chronic hyperglycemia frequently prevent mitophagy in diabetic individuals. This inhibition exacerbates cellular dysfunction and disturbance of energy metabolism, leads to the accumulation of damaged mitochondria, and sets off inflammatory reactions and apoptosis[118-121].

The health of keratinocytes and fibroblasts in skin tissue is directly impacted by impaired mitophagy. The function of the epidermal barrier and wound healing depend on these cells. Cellular oxidative stress rises when damaged mitochondria cannot be eliminated, consequently impairing cellular structure and function. In addition to delaying wound healing, this could encourage the development of persistent ulcers. Furthermore, diabetes-related neuropathy and vasculopathy worsen the severity of skin ulcers by impairing nerve conduction and lowering the local blood supply[56,94,120].

More and more recent research has concentrated on the specific mechanisms of mitophagy in diabetic skin ulcers. In diabetic mice, studies have shown that controlling important mitophagy proteins including PINK1 and PARKIN greatly enhances skin healing. These results suggest that the integrity and functionality of skin cells are maintained in large part by mitophagy. In addition to encouraging the regeneration and repair of damaged tissue, activation of the mitophagy pathway can lower the risk of complications from diabetes[91,94].

Furthermore, cellular energy consumption and signal transduction are closely related to mitophagy. In addition to being unable to produce energy effectively, damaged mitochondria in diabetics also release an excessive amount of ROS, which damages large areas of tissue. At the most basic level, the pathological state of skin ulcers can be improved by promoting mitophagy, which can efficiently remove these dangerous mitochondria and restore normal cellular function and metabolic balance[123].

However, there is still a significant information gap about mitophagy in human diabetic foot ulcer tissue, as evidenced by the paucity of available data. Future research should examine mitochondrial DNA damage, mitophagy-specific transcriptomics, PINK1/PARKIN colocalization, and electron microscopy in human tissue samples to confirm the mechanistic findings[132].

In conclusion, mitophagy represents a critical regulatory mechanism underlying the pathogenesis of diabetes-associated skin ulcers, particularly through its role in maintaining mitochondrial quality control under conditions of chronic hyperglycemia, hypoxia, and inflammation. Further elucidation of mitophagy regulatory networks and their cell-type-specific functions in skin tissues may provide a theoretical foundation for the development of innovative therapeutic strategies aimed at improving wound healing outcomes in patients with diabetes[87,94].

Beyond skin complications, accumulating evidence also suggests that dysregulated mitophagy contributes to diabetes-related cognitive impairment, highlighting mitophagy as a shared pathological link across distinct diabetic complications. Future mechanistic studies are therefore required to clarify the origins and heterogeneity of mitophagy phenotypes observed in both diabetic skin ulcers and cognitive dysfunction, as well as to determine whether common or tissue-specific regulatory pathways are involved.

From a translational perspective, priority research directions include the identification of reliable mitophagy-related biomarkers, optimization of therapeutic timing and intervention windows, and the implementation of well-designed clinical studies to validate findings from preclinical models. Integrating mitophagy-targeted interventions with established diabetes management strategies may ultimately offer novel avenues for preventing and treating these debilitating complications while enhancing clinical relevance and therapeutic precision.

Beyond classical pharmacological agents such as rapamycin and metformin, emerging therapeutic strategies targeting mitophagy are being actively explored. These include mitochondrial-targeted antioxidants, modulation of mitophagy-related signaling pathways, and gene-based approaches aimed at restoring mitochondrial quality control. Recent advances in gene editing technologies, such as CRISPR-Cas9, have also raised the possibility of selectively manipulating key mitophagy regulators; however, such strategies remain largely experimental and require careful evaluation of safety and feasibility[89,91].

Importantly, several challenges hinder the direct translation of mitophagy-targeted interventions from preclinical models to clinical practice. These include the lack of reliable and noninvasive biomarkers to monitor mitophagy activity in patients, uncertainty regarding optimal timing and dosage of interventions, and potential tissue-specific or context-dependent effects of mitophagy modulation. Moreover, diabetes is a multifactorial systemic disease, suggesting that mitophagy-targeted therapies may be most effective when integrated with established metabolic control strategies rather than applied as standalone treatments. These discrepancies highlight the tissue-specific and stage-dependent nature of mitophagy regulation, underscoring the need to interpret mechanistic findings in light of clinical context rather than extrapolating from single disease models.

CONCLUSION

Dysregulated mitophagy is a shared pathogenic mechanism contributing to both diabetes-related cognitive impairment and impaired skin-ulcer healing by compromising mitochondrial quality control under chronic metabolic stress. Targeting mitophagy therefore represents a promising therapeutic avenue to restore neuronal resilience and improve wound repair, but effective translation will require defining disease- and stage-specific “optimal” mitophagy rather than indiscriminate activation or inhibition. Next steps toward clinical application include establishing accessible mitophagy-related biomarkers, identifying appropriate therapeutic windows, and validating mitophagy-modulating strategies in well-designed human studies relevant to cognitive outcomes and diabetic wound healing. Future studies should prioritize validation of mitophagy-related mechanisms in human populations, followed by the identification of reliable circulating or tissue-based biomarkers and the definition of optimal therapeutic windows. Such efforts will be essential for translating mitophagy-targeted strategies into clinically feasible interventions for diabetes-related cognitive impairment and skin ulcers.